Hepatic disease is a major cause of morbidity in western countries. Hepatitis C, for example, is transmitted by blood contamination and many current cases represent infection from blood transfusion prior to universal blood testing. Most new cases are drug (of addiction) related. About 80% of those affected develop chronic hepatitis (20% with cirrhosis) while about 10% will eventually develop hepatoma. Until recently, the only effective therapy has been interferon, which is expensive, is given parentally, has many side effects, and is of limited value.
Alcohol consumption can lead to hepatic disorders. It affects normal immune function, especially cell-mediated immunity1-3. T cells play an important role in the progression of alcohol-related disease4-6. Studies of alcoholic liver disease in humans and animals have shown that T cell proliferation is significantly altered in response to mitogens such as concanavalin A (Con A) or phytohemagglutinin (PHA) in vitro7-9. In rats or mice fed alcohol, the blood T cell proliferative response to Con A stimulation was depressed whereas the response to PHA was elevated, with CD4+ T helper cells being the responding cell type2,3,8,10. This suggests that the level of T-cell activation10, the responding cell phenotype3, and the pattern of cytokine secretion11 following exposure to ethanol probably all play a role in alcohol related liver disease. Ethanol-fed rats injected with Con A developed more severe hepatic necrosis with infiltration of CD4+ and CD8+ T cells in the portal vein and central vein areas compared with sucrose or isocaloric sucrose fed rats. In these rats increased numbers of activated liver-associated CD4+ T cells secreting high levels of TNF-α and IL-6 in culture were observed4-6. These alcohol-fed rats have been used as a basic research tool to study the role of T lymphocytes in the onset of liver damage.
While it is hypothesised that the level of T-cell activation, the responding cell phenotype, and the pattern of cytokine secretion following exposure to ethanol may all play a role in alcohol-associated liver disease, it is noted that such diseases are complex in nature. As such many other as yet unidentified factors are likely to contribute to the presentation of the disease. Thus, further research is necessary to elucidate the precise cellular and biochemical mechanisms and interactions involved in the initiation and progression of the disease. Further, it is noted that the precise cellular and biochemical mechanisms and interactions involved in alcohol-induced hepatitis are likely to be different to the precise mechanisms involved in pathogen-mediated hepatitis, such as hepatitis C, and auto-immune hepatic disorders.
Treatment for many hepatic disorders is clearly unsatisfactory and there is an urgent need for improved therapeutics. Consequently there is also a need for suitable methods and in particular animal models to predict the therapeutic value of potentially useful compounds.
It is an object of the present invention to provide an animal model, methods and therapeutic compounds which may overcome or substantially ameliorate at least some of the deficiencies of the prior art, or will provide a useful alternative.